Imidazole derivatives

ABSTRACT

The present invention relates to compounds of formula I 
     
       
         
         
             
             
         
       
     
     wherein
     R 1′  is CH 3 ;   R 1  is methyl, ethyl, CF 3 , cyclopropyl, CH 2 OH or
       R 1′  and R 1  may form together with the carbon atom to which they are attached a 1,1-dioxo-thiolan-3-yl ring;   
       R 2  is hydrogen, methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH 2 OH or C(CH 3 ) 2 OH;   R 3  is Cl, F, CF 3 , cyano, methyl or cyclopropyl;   R 4  is hydrogen, methyl or F;
 
or to a pharmaceutically acceptable salt or acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof for use in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder.

The present invention relates to compounds of formula I

wherein

-   R^(1′) is CH₃;-   R¹ is methyl, ethyl, CF₃, cyclopropyl, CH₂OH or    -   R^(1′) and R¹ may form together with the carbon atom to which        they are attached a 1,1-dioxo-thiolan-3-yl ring;-   R² is hydrogen, methyl, ethyl, isopropyl, tertbutyl, cyclopropyl,    CH₂OH or C(CH₃)₂OH;-   R³ is Cl, F, CF₃, cyano, methyl or cyclopropyl;-   R⁴ is hydrogen, methyl or F;    or to a pharmaceutically acceptable salt or acid addition salt, to a    racemic mixture, or to its corresponding enantiomer and/or optical    isomer and/or stereoisomer thereof for use in the treatment of    psychiatric disorders such as schizophrenia, bipolar disorder,    obsessive-compulsive disorder or autism spectrum disorder.

It has been surprisingly been found that the compounds of generalformula I are EAAT3 inhibitors.

The excitatory amino acid transporter 3 (EAAT3), also referred to inhuman studies as solute carrier family 1, member 1 (systematic genename: SLC1A1) and in rodents as excitatory amino acid carrier 1 (EAAC1),is a high-affinity anionic amino acid transporter found in neuronsthroughout the cortex and in the hippocampus, basal ganglia (striatum,thalamus), and the olfactory bulb. EAAT3 functions to buffer localglutamate concentrations at excitatory synapses, for example in thehippocampus, and modulates the differential recruitment of glutamatereceptor subtypes at extrasynaptic sites. Furthermore, EAAT3 is thoughtto be involved in facilitating GABA and glutathione biosynthesis. EAAT3is a member of the EAAT family that mediates the uptake of glutamateinto neuronal and glial cells of the mammalian CNS. Two transportersexpressed primarily in glia, EAAT1 and EAAT2, are crucial for glutamatehomeostasis in the adult mammalian brain and for rapid clearance ofglutamate from the synaptic cleft. Three neuronal transporters (EAAT3,EAAT4, and EAAT5) appear to have additional functions in regulating andprocessing cellular excitability with EAAT3 being abundantly expressedthroughout the CNS (EAAT4 is unique to Purkinje cells of the cerebellumand EAAT5 is expressed in rod photoreceptor and bipolar cells of theretina).

EAATs are assembled as trimers, and the existence of multiple isoformsraises the question of whether certain isoforms can formhetero-oligomers. In the mammalian brain, the specificity of excitatorysynaptic transmission depends on rapid diffusion of glutamate away fromactive synapses and the powerful uptake capacity of glutamatetransporters in astrocytes. The extent to which neuronal glutamatetransporters influence the lifetime of glutamate in the extracellularspace remains unclear, but it is thought to be minor. EAAT3, thepredominant neuronal glutamate transporter at excitatory synapses inhippocampal area CA1, buffers glutamate released during synaptic eventsand prolongs the time course of its clearance by astrocytes. EAAT3 doesnot significantly alter activation of receptors in the synaptic cleft.Instead, it reduces recruitment of perisynaptic/extrasynapticNR2B-containing NMDARs, thereby facilitating induction of long-termpotentiation by short bursts of high-frequency stimulation. SpecificEAAT3 inhibitors may have the potential to locally and specificallystrengthen particular synapses.

Obsessive-compulsive disorder (OCD) is among the most common mentaldisorders (prevalence 1-3%), and is at least as prevalent asschizophrenia and bipolar disorder. In the United States, one in 50adults suffers from OCD. OCD affects children and adolescents as well asadults. Roughly one third to one half of adults with OCD reports achildhood onset of the disorder, and the disorder is typically chronicin nature. Treatment consists of predominantly serotonergic TCAs(clomipramine) or SSRIs in combination with cognitive-behavioral therapy(CBT). Overall, response to these interventions is of some but stilllimited benefit (approximately comparable to antidepressant response inMDD), and given the chronicity of OCD, the unmet medical need remainsvery high. OCD has been linked to serotonin and glutamate abnormalities.The hypothesis of glutamate signaling dysfunction in OCD is based onfindings from neuroimaging, animal models, positional cloning andtreatment studies.

The obsessive-compulsive symptomatology in OCD has considerablephenomenological, epidemiological and possibly(aetio)-pathophysiological overlap with a core autism spectrum disordercriterion: “restricted, repetitive patterns of behavior, interests, oractivities” (taken from proposed DSM-5 revision). In support of thisnotion, human genetics studies have linked both the serotonintransporter and EAAT3 (SLC1A1) genes to autism spectrum disorder (ASD)or rigid-compulsive behavior in ASD and to OCD.

In addition, obsessive-compulsive symptoms induced by antipsychotics inschizophrenic bipolar disorder patients have been linked to EAAT3(SLC1A1) gene variants. Post-mortem brain studies have shown that bothclassic and atypical antipsychotics reduce EAAT3, suggesting aninvolvement of this transporter in neuroleptic mechanisms beyonddopamine and serotonin modulation. Moreover, genetic variation in thehuman gene EAAT3 (SLC1A1) has been associated with antipsychotic drugresponse.

There is converging evidence from neurobiological data, human genetics,imaging studies and experimental treatments that EAAT3 is a keypathophysiological element in OCD and rigid-compulsive behavior inautism and in schizophrenia.

-   Curr. Opin. Pharmacol. 20, 116-123, 2015-   J. Neurosci., 32, 2552-2563, 2012-   J. Neurosci 29, 14581-14595, 2009-   Arch. Gen. Psychiatry, 66, 408-416, 2009-   Pharmacol. Ther. 107, 271-285, 2005-   J. Neurochem. 98, 1007-1018, 2006-   Nat. Neurosci., 9, 119-126, 2006

Compounds of formula I are distinguished by having valuable therapeuticproperties. They can be used in the treatment or prevention ofdisorders, relating to EAAT3 inhibitors.

The most preferred indications for compounds which are EAAT3 inhibitorsare psychiatric disorders such as schizophrenia, bipolar disorder,obsessive-compulsive disorder or autism spectrum disorder.

The present invention relates to compounds of formula I and to theirpharmaceutically acceptable salts for use in the treatment ofpsychiatric disorders such as schizophrenia, bipolar disorder,obsessive-compulsive disorder or autism spectrum disorder, to compoundsof formulas IA, IB, IC, ID, IE and IF as pharmaceutically activesubstances, to the processes for their production as well as to theiruse in the treatment or prevention of disorders, relating to EAAT3inhibitors, such as schizophrenia, bipolar disorder,obsessive-compulsive disorder or autism spectrum disorder and topharmaceutical compositions containing the compounds of formulas IA, IB,IC, ID, IE and IF.

A further object of the present invention is a method for the treatmentor prophylaxis of psychiatric disorder such as schizophrenia, bipolardisorder, obsessive-compulsive disorder or autism spectrum disorder,which method comprises administering an effective amount of a compoundof formula I to a mammal in need.

Furthermore, the invention includes all racemic mixtures, all theircorresponding enantiomers and/or optical isomers, or analoguescontaining isotopes of hydrogen, fluorine, carbon, oxygen or nitrogen.

One object of the present invention are novel compounds of formula IA,

whereinR² is hydrogen, methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH₂OHor C(CH₃)₂OH;R³ is Cl, F, CF₃, cyano, methyl or cyclopropyl;R⁴ is hydrogen, methyl or F;or a pharmaceutically acceptable salt or acid addition salt, a racemicmixture, or its corresponding enantiomer and/or optical isomer and/orstereoisomer thereof, for example the following compounds:

-   N-tert-Butyl-3-(4-chlorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide-   N-tert-Butyl-3-(4-chlorophenyl)-5-imidazol-1-ylbenzamide-   N-tert-Butyl-3-(4-chlorophenyl)-5-(2-methylimidazol-1-yl)-benzamide-   N-tert-Butyl-3-(4-chlorophenyl)-5-(2-ethylimidazol-1-yl)-benzamide-   N-tert-Butyl-3-(4-chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-benzamide-   N-tert-Butyl-3-(4-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide-   N-tert-Butyl-3-(2-ethylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide-   N-tert-Butyl-3-(4-fluorophenyl)-5-(2-methylimidazol-1-yl)-benzamide-   N-tert-Butyl-3-(2-cyclopropylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide-   N-tert-Butyl-3-(2-propan-2-ylimidazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide-   N-tert-Butyl-3-(3-fluoro-4-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide-   N-tert-Butyl-3-(3,4-difluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide-   N-tert-Butyl-3-(4-chloro-3-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide-   N-tert-Butyl-3-(4-cyclopropylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide-   N-tert-Butyl-3-(4-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide-   N-tert-Butyl-3-(4-fluoro-3-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide-   N-tert-Butyl-3-(2-tert-butylimidazol-1-yl)-5-(4-chlorophenyl)-benzamide-   N-tert-Butyl-3-(4-chlorophenyl)-5-[2-(hydroxymethyl)-imidazol-1-yl]-benzamide-   N-tert-Butyl-3-(2-tert-butylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide-   N-tert-Butyl-3-(2-tert-butylimidazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide-   N-tert-Butyl-3-(4-fluorophenyl)-5-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-benzamide-   N-tert-Butyl-3-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-5-[4-(trifluoromethyl)-phenyl]-benzamide    or-   N-tert-Butyl-3-(4-chlorophenyl)-5-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-benzamide

One further object of the present invention are novel compounds offormula IB,

whereinR² is hydrogen, methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH₂OHor C(CH₃)₂OH;R³ is Cl, F, CF₃, cyano, methyl or cyclopropyl;R⁴ is hydrogen, methyl or F;or a pharmaceutically acceptable salt or acid addition salt, a racemicmixture, or its corresponding enantiomer and/or optical isomer and/orstereoisomer thereof, for example the compounds

-   3-(4-Chlorophenyl)-5-[2-(hydroxymethyl)-imidazol-1-yl]-N-(2-methylbutan-2-yl)-benzamide-   3-(2-tert-Butylimidazol-1-yl)-5-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-benzamide-   3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide    or-   3-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(2-methylbutan-2-yl)-benzamide.

One object of the present invention are novel compounds of formula IC,

whereinR² is hydrogen, methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH₂OHor C(CH₃)₂OH;R³ is Cl, F, CF₃, cyano, methyl or cyclopropyl;R⁴ is hydrogen, methyl or F;or a pharmaceutically acceptable salt or acid addition salt, a racemicmixture, or its corresponding enantiomer and/or optical isomer and/orstereoisomer thereof, for example the compounds

-   3-(4-Chlorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide-   3-(4-Chlorophenyl)-5-(2-methylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide    or-   3-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide.

One object of the present invention are novel compounds of formula ID,

whereinR² is hydrogen, methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH₂OHor C(CH₃)₂OH;R³ is Cl, F, CF₃, cyano, methyl or cyclopropyl;R⁴ is hydrogen, methyl or F;or a pharmaceutically acceptable salt or acid addition salt, a racemicmixture, or its corresponding enantiomer and/or optical isomer and/orstereoisomer thereof, for example the compounds

-   3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide-   3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-ethylimidazol-1-yl)-benzamide-   3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-methylimidazol-1-yl)-benzamide-   3-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(2-cyclopropyl-propan-2-yl)-benzamide-   N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide-   N-(2-Cyclopropylpropan-2-yl)-3-(2-ethylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide-   N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(2-methylimidazol-1-yl)-benzamide    or-   3-(2-Cyclopropylimidazol-1-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide.

One further object of the invention are compounds of formula IE,

whereinR² is hydrogen, methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH₂OHor C(CH₃)₂OH;R³ is Cl, F, CF₃, cyano, methyl or cyclopropyl;R⁴ is hydrogen, methyl or F;or a pharmaceutically acceptable salt or acid addition salt, a racemicmixture, or its corresponding enantiomer and/or optical isomer and/orstereoisomer thereof, for example the compounds

-   (RS)-3-(4-Chlorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide    or-   (RS)-3-(4-chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide.    One further object of the invention are compounds of formula IF,

whereinR² is hydrogen, methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH₂OHor C(CH₃)₂OH;R³ is Cl, F, CF₃, cyano, methyl or cyclopropyl;R⁴ is hydrogen, methyl or F;or a pharmaceutically acceptable salt or acid addition salt, a racemicmixture, or its corresponding enantiomer and/or optical isomer and/orstereoisomer thereof, for example the compounds

-   3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(2-propan-2-yl-imidazol-1-yl)-benzamide-   3-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide    or-   3-(2-tert-Butylimidazol-1-yl)-5-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide.

The preparation of compounds of formulas IA, IB, IC, ID, IE and IF ofthe present invention may be carried out in sequential or convergentsynthetic routes. Syntheses of the compounds of the invention are shownin the following schemes 1 to 4. The skills required for carrying outthe reaction and purification of the resulting products are known tothose skilled in the art. The substituents and indices used in thefollowing description of the processes have the significance givenherein before.

The compounds of formulas IA, IB, IC, ID, IE and IF can be manufacturedby the methods given below, by the methods given in the examples or byanalogous methods. Appropriate reaction conditions for the individualreaction steps are known to a person skilled in the art. The reactionsequence is not limited to the one displayed in the schemes, however,depending on the starting materials and their respective reactivity thesequence of reaction steps can be freely altered. Starting materials areeither commercially available or can be prepared by methods analogous tothe methods given below, by methods described in references cited in thedescription or in the examples, or by methods known in the art.

The present compounds of formulas IA, IB, IC, ID, IE and IF and theirpharmaceutically acceptable salts may be prepared by methods, known inthe art, for example by the process variant described below, whichprocess comprises

a) reacting a compound of formula

with a compound of formula

to a compound of formula I

wherein the substituents are as described above, orif desired, converting the compounds obtained into pharmaceuticallyacceptable acid addition salts.

b) reacting a compound of formula

with a compound of formula

to a compound of formula I

wherein the substituents are described above, orif desired, converting the compounds obtained into pharmaceuticallyacceptable acid addition salts.

The preparation of compounds of formulas IA, IB, IC, ID, IE and IF isfurther described in more detail in scheme 1 to 4 and in examples 1-43.

The imidazole derivatives I can either be prepared from the intermediateiodo derivatives II by substitution reaction with commercially availableimidazoles III.

or by coupling reaction of the iodo derivatives IV with commerciallyavailable boronic acid derivatives V.

The iodo derivatives II can be prepared starting from commerciallyavailable 3-iodo-5-nitrobenzoic acid VI. Amide formation with thecommercially available amines VII using standard conditions leads to theamides VIII which can coupled with commercially available boronic acidderivatives III to yield the nitro compounds IX which can be reducedwith tin(II)chloride to yield the aniline derivatives X. Well knowntransformation of the aniline into iodine leads to the iodo buildingblocks II.

The synthesis of the iodo derivatives IV can start from the abovedescribed iodo derivatives VIII which can be transformed into theimidazole derivatives XI by substitution reaction with commerciallyavailable imidazoles III. Reduction of the nitro group to the aniline asdescribed above leads to the derivatives XII. The iodo derivatives IVcan be prepared from derivatives XII by known transformation of theaniline into the iodine.

Generally speaking, the sequence of steps used to synthesize thecompounds of formula I can also be modified in certain cases.

The compounds of formula I and their pharmaceutically usable additionsalts possess valuable pharmaceutical properties. Specifically, it hasbeen found that the compounds of the present invention are EAAT3inhibitors for use in the treatment of schizophrenia, bipolar disorder,obsessive-compulsive disorder or autism spectrum disorders. Thecompounds were investigated in accordance with the test givenhereinafter.

Biological Assay and Data The FLIPR Membrane Potential (FMP) Assay

HEK-293 cells stably expressing human EAAT3 were seeded at 55 000cells/well in growth medium (DMEM glutamate free (Invitrogen 11960-044),1% Pen Strep (10 ml/1 GIBCO BRL N^(o) 15140-023), 10% FCS non dialysedheat inactivated, 5 mg/l puromycin) in poly-D-lysine treated 96-wellblack microtiter plates with clear-bottom. After 24 h, the growth mediumwas removed and 100 μl/well of Krebs buffer (140 mM NaCl, 4.7 mM KCl,2.5 mM CaCl₂, 1.2 mM MgCl₂, 11 mM HEPES, 10 mM D-glucose, pH=7.4) added.The cells were then loaded by adding 100 μl/well FMP assay dye (FLIPRMembrane Potential assay reagent, Molecular Devices). The 96-well plateswere then incubated at 37° C. for 1 h. The depolarization of the cellswill cause more dye to enter in the cells, where it will bind tointracellular proteins and lipids and cause an increase in thefluorescence signal. Antagonist potency at human EAAT3 was determined byusing L-glutamate as agonist at a concentration which gives 80% of themaximum response. The antagonists were applied 15 min before theapplication of the agonist L-glutamate. The assays were performed atroom temperature and measurements done by using a Fluorometric ImagingPlate Reader (FLIPR, Molecular Devices) and filter #2. Responses weremeasured as peak increase in fluorescence minus basal (i.e. fluorescencewithout addition of L-glutamate). Kb was determined using theCheng-Prusoff equation Kb=IC₅₀/[1+(A/EC₅₀)], where IC₅₀ is theconcentration of the antagonist producing 50% inhibition, A is theconcentration of the agonist against which the IC₅₀ is being determined(at EC₈₀) and EC₅₀ is the concentration of the agonist producing 50%inhibition.

List of Examples and Data:

EAAT3 Kb Structure Compound name [uM] 1

N-tert-Butyl-3-(4-chlorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide 0.18 2

N-tert-Butyl-3-(4-chlorophenyl)-5- imidazol-1-ylbenzamide 0.23 3

N-tert-Butyl-3-(4-chlorophenyl)-5-(2- methylimidazol-1-yl)-benzamide0.19 4

N-tert-Butyl-3-(4-chlorophenyl)-5-(2- ethylimidazol-1-yl)-benzamide 0.185

N-tert-Butyl-3-(4-chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-benzamide 0.12 6

N-tert-Butyl-3-(4-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide 0.076 7

3-(4-Chlorophenyl)-5-(2-propan-2- ylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide 0.2 8

3-(4-Chlorophenyl)-N-(2- cyclopropylpropan-2-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide 0.23 9

3-(4-Chlorophenyl)-N-(2- cyclopropylpropan-2-yl)-5-(2-ethylimidazol-1-yl)-benzamide 0.22 10

N-tert-Butyl-3-(2-ethylimidazol-1-yl)- (4-fluorophenyl)-benzamide 0.1111

3-(4-Chlorophenyl)-N-(2- cyclopropylpropan-2-yl)-5-(2-methylimidazol-1-yl)-benzamide 0.17 12

N-tert-Butyl-3-(4-fluorophenyl)-5-(2- methylimidazol-1-yl)-benzamide0.13 13

3-(4-Chlorophenyl)-5-(2- cyclopropylimidazol-1-yl)-N-(2-cyclopropyl-propan-2-yl)-benzamide 0.31 14

3-(4-Chlorophenyl)-5-(2- methylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)- benzamide 0.13 15

3-(4-Chlorophenyl)-5-(2- cyclopropylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)- benzamide 0.15 16

N-tert-Butyl-3-(2-cyclopropylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide 0.13 17

N-(2-Cyclopropylpropan-2-yl)-3-(4- fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide 0.12 18

N-(2-Cyclopropylpropan-2-yl)- 3-(2-ethylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide 0.17 19

N-(2-Cyclopropylpropan-2-yl)-3-(4- fluorophenyl)-5-(2-methylimidazol-1-yl)-benzamide 0.29 20

3-(2-Cyclopropylimidazol-1-yl)-N-(2- cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide 0.033 21

N-tert-Butyl-3-(2-propan-2-ylimidazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]- benzamide 0.18 22

N-tert-Butyl-3-(3-fluoro-4- methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide 0.12 23

N-tert-Butyl-3-(3,4-difluorophenyl)- 5-(2-propan-2-ylimidazol-1-yl)-benzamide 0.15 24

N-tert-Butyl-3-(4-chloro-3- fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide 0.19 25

N-tert-Butyl-3-(4-cyclopropylphenyl)- 5-(2-propan-2-ylimidazol-1-yl)-benzamide 0.21 26

N-tert-Butyl-3-(4-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide 0.13 27

N-tert-Butyl-3-(4-fluoro-3- methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide 0.28 28

N-tert-Butyl-3-(2-tert-butylimidazol- 1-yl)-5-(4-chlorophenyl)-benzamide0.16 29

N-tert-Butyl-3-(4-chlorophenyl)-5-[2- (hydroxymethyl)-imidazol-1-yl]-benzamide 0.15 30

3-(4-Chlorophenyl)-5-[2- (hydroxymethyl)-imidazol-1-yl]-N-(2-methylbutan-2-yl)-benzamide 0.16 31

3-(2-tert-Butylimidazol-1-yl)-5-(4- chlorophenyl)-N-(2-methylbutan-2-yl)-benzamide 0.41 32

N-tert-Butyl-3-(2-tert-butylimidazol-1- yl)-5-(4-fluorophenyl)-benzamide0.18 33

N-tert-Butyl-3-(2-tert-butylimidazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]- benzamide 0.29 34

N-tert-Butyl-3-(4-fluorophenyl)-5-[2- (2-hydroxypropan-2-yl)-imidazol-1-yl]-benzamide 0.1 35

N-tert-Butyl-3-[2-(2-hydroxypropan- 2-yl)-imidazol-1-yl]-5-[4-(trifluoromethyl)-phenyl]-benzamide 0.21 36

3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-(2-propan-2-ylimidazol-1-yl)- benzamide 0.33 37

3-(4-Chlorophenyl)-5-(2- cyclopropylimidazol-1-yl)-N-(2-methylbutan-2-yl)-benzamide 0.17 38

(RS)-3-(4-Chlorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-5-(2-propan-2- ylimidazol-1-yl)-benzamide 0.22 39

(RS)-3-(4-chlorophenyl)-5-(2- cyclopropylimidazol-1-yl)-N-(3-methyl-1,1-dioxothiolan-3-yl)- benzamide 0.18 40

N-tert-Butyl-3-(4-chlorophenyl)-5-[2- (2-hydroxypropan-2-yl)-imidazol-1-yl]-benzamide 0.07 41

3-(4-Chlorophenyl)-N-(1-hydroxy-2- methylpropan-2-yl)-5-(2-propan-2-yl-imidazol-1-yl)-benzamide 0.54 42

3-(4-Chlorophenyl)-5-(2- cyclopropylimidazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)- benzamide 0.17 43

3-(2-tert-Butylimidazol-1-yl)-5-(4- chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide 0.08

The compounds of formula (I) and pharmaceutically acceptable saltsthereof can be used as medicaments, e.g. in the form of pharmaceuticalpreparations. The pharmaceutical preparations can be administeredorally, e.g. in the form of tablets, coated tablets, dragees, hard andsoft gelatine capsules, solutions, emulsions or suspensions. However,the administration can also be effected rectally, e.g. in the form ofsuppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof can be processed with pharmaceutically inert, inorganic ororganic carriers for the production of pharmaceutical preparations.Lactose, corn starch or derivatives thereof, talc, stearic acid or itssalts and the like can be used, for example, as such carriers fortablets, coated tablets, dragées and hard gelatin capsules. Suitablecarriers for soft gelatin capsules are, for example, vegetable oils,waxes, fats, semi-solid and liquid polyols and the like; depending onthe nature of the active substance no carriers are, however, usuallyrequired in the case of soft gelatin capsules. Suitable carriers for theproduction of solutions and syrups are, for example, water, polyols,sucrose, invert sugar, glucose and the like. Adjuvants, such asalcohols, polyols, glycerol, vegetable oils and the like, can be usedfor aqueous injection solutions of water-soluble salts of compounds offormula (I), but as a rule are not necessary. Suitable carriers forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

As mentioned earlier, medicaments containing a compound of formula (I)or pharmaceutically acceptable salts thereof and a therapeutically inertexcipient are also an object of the present invention, as is a processfor the production of such medicaments which comprises bringing one ormore compounds of formula I or pharmaceutically acceptable salts thereofand, if desired, one or more other therapeutically valuable substancesinto a galenical dosage form together with one or more therapeuticallyinert carriers.

As further mentioned earlier, the use of the compounds of formula (I)for the preparation of medicaments useful in the prevention and/or thetreatment of the above recited diseases is also an object of the presentinvention.

The dosage can vary within wide limits and will, of course, be fitted tothe individual requirements in each particular case. In general, theeffective dosage for oral or parenteral administration is between0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred forall of the indications described. The daily dosage for an adult humanbeing weighing 70 kg accordingly lies between 0.7-1400 mg per day,preferably between 7 and 700 mg per day.

Preparation of Pharmaceutical Compositions Comprising Compounds of theInvention

Tablets of the following composition are manufactured in the usualmanner:

mg/tablet ingredient 5 25 100 500 Compound of formula I 5 25 100 500Lactose Anhydrous DTG 125 105 30 150 Sta-Rx 1500 6 6 6 60Microcrystalline Cellulose 30 30 30 450 Magnesium Stearate 1 1 1 1 Total167 167 167 831

Manufacturing Procedure

1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.2. Dry the granules at 50° C.3. Pass the granules through suitable milling equipment.4. Add ingredient 5 and mix for three minutes; compress on a suitablepress.

Capsules of the Following Composition are Manufactured:

mg/capsule ingredient 5 25 100 500 Compound of formula I 5 25 100 500Hydrous Lactose 159 123 148 — Corn Starch 25 35 40 70 Talk 10 15 10 25Magnesium Stearate 1 2 2 5 Total 200 200 300 600

Manufacturing Procedure

1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.2. Add ingredients 4 and 5 and mix for 3 minutes.3. Fill into a suitable capsule.

A compound of formula I lactose and corn starch are firstly mixed in amixer and then in a comminuting machine. The mixture is returned to themixer; the talc is added thereto and mixed thoroughly. The mixture isfilled by machine into suitable capsules, e.g. hard gelatin capsules.

Injection Solutions of the Following Composition are Manufactured:

ingredient mg/injection solution. Compound of formula I 3 PolyethyleneGlycol 400 150 acetic acid q.s. ad pH 5.0 water for injection solutionsad 1.0 ml

Manufacturing Procedure

A compound of formula I is dissolved in a mixture of Polyethylene Glycol400 and water for injection (part). The pH is adjusted to 5.0 by aceticacid. The volume is adjusted to 1.0 ml by addition of the residualamount of water. The solution is filtered, filled into vials using anappropriate overage and sterilized.

EXPERIMENTAL SECTION Intermediates Intermediate 1:N-tert-Butyl-3-(4-chlorophenyl)-5-iodobenzamide Step A

To a stirred solution of commercially available 3-iodo-5-nitrobenzoicacid (2 g, 6.83 mmol) in THF (49.1 ml) was added at room temperatureN,N-diisopropylethylamine (2.21 g, 2.98 ml, 17.1 mmol),2-methylpropan-2-amine (611 mg, 878 μl, 8.19 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (3.51 g, 10.9 mmol). The reaction mixture was stirred at roomtemperature for 4 h, evaporated and the residue purified by flashchromatography on silica gel [heptane/ethyl acetate (0-50%)] to yieldN-tert-butyl-3-iodo-5-nitrobenzamide (2.31 g, 97%) as an off-whitesolid, MS (ISP) m/z=349.0 [(M+H)⁺], mp 166° C.

Step B

A mixture of N-tert-butyl-3-iodo-5-nitrobenzamide (2.3 g, 6.61 mmol) and(4-chlorophenyl)boronic acid (1.34 g, 8.59 mmol) in 1,2-dimethoxyethane(44 ml) and 2M Na₂CO₃ (11 ml, 22 mmol) was purged with argon in anultrasonic bath for 5 min, triphenylphosphine (347 mg, 1.32 mmol) andpalladium(II)acetate (148 mg, 661 μmol) were added and the reactionmixture was stirred for 3 h under reflux conditions. The reactionmixture poured into water (50 ml) and extracted with ethylacetate (2×50ml). The combined organic layers were washed with brine (40 ml), dried(MgSO₄) and evaporated to give the crude product (3.09 g) as brownsolid, which was purified by flash chromatography on silica gel[heptane/ethyl acetate (0-50%)] to yieldN-tert-butyl-3-(4-chlorophenyl)-5-nitrobenzamide (2.38 g, 92%) as abrown solid, MS (ISP) m/z=333.1 [(M+H)⁺], mp 186° C.

Step C

To a stirred solution ofN-tert-butyl-3-(4-chlorophenyl)-5-nitrobenzamide (2.38 g, 6.58 mmol) inMeOH (49.8 ml) was added at room temperature tin(II)chloride dihydrate(5.94 g, 26.3 mmol) and the reaction mixture was stirred under refluxconditions for 2 h, evaporated, water (50 ml) and 2N NaOH (50 ml) wereadded and the mixture was extracted with ethyl acetate (2×75 ml). Thecombined organic layers were washed with water (50 ml) and brine (50ml), dried (MgSO₄) and evaporated. The crude product (brown solid, 2.08g) was purified by flash chromatography on silica gel[dichloromethane/MeOH (1-5%)] to yield3-amino-N-tert-butyl-5-(4-chlorophenyl)-benzamide (1.90 g, 95%) as alight brown solid, MS (ISP) m/z=303.1 [(M+H)⁺], mp 231° C.

Step D

A mixture of 3-amino-N-tert-butyl-5-(4-chlorophenyl)-benzamide (1.899 g,6.27 mmol), isoamyl nitrite (4.59 g, 5.27 ml, 37.6 mmol) anddiiodomethane (10.2 g, 3.07 ml, 37.6 mmol) was stirred at roomtemperature for 1 h, and afterwards at 65° C. for 5 h. The reactionmixture was cooled to room temperature, toluene (30 ml) was added andthe mixture was evaporated to dryness which was repeated 3 times. Theresidue was purified by flash chromatography on silica gel [heptane/ethyacetate (0-40%)] to yield the title compound (1.41 g, 55%) as lightyellow foam, MS (ISP) m/z=414.0 [(M+H)⁺].

Intermediate 2:(RS)-3-(4-Chlorophenyl)-5-iodo-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamideStep A

3-(4-Chlorophenyl)-5-nitrobenzoic acid, light yellow solid (3.29 g,99%), MS (ISN) m/z=276.1 [(M−H)⁻], mp 206° C., was prepared inaccordance with the general method of intermediate 1, step B, fromcommercially available 3-iodo-5-nitrobenzoic acid (3.66 g, 11.9 mmol)and commercially available (4-chlorophenyl)-boronic acid (2.04 g, 13.1mmol).

Step B

(RS)-3-(4-Chlorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-5-nitrobenzamide,light yellow foam (1.41 g, 91%), MS (ISP) m/z=409.1 [(M+H)⁺], wasprepared in accordance with the general method of intermediate 1, stepA, from 3-(4-chlorophenyl)-5-nitrobenzoic acid (1.05 g, 3.78 mmol) andcommercially available (RS)-3-amino-3-methyltetrahydrothiophene1,1-dioxide (677 mg, 4.54 mmol).

Step C

(RS)-3-Amino-5-(4-chlorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide,white solid (1.19 g, 91%), MS (ISP) m/z=379.1 [(M+H)⁺], mp 197° C., wasprepared in accordance with the general method of intermediate 1, stepC, from(RS)-3-(4-chlorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-5-nitrobenzamide(1.41 g, 3.45 mmol).

Step D

The title compound, off-white foam (1.175 g, 77%), MS (ISP) m/z=490.1[(M+H)⁺], was prepared in accordance with the general method ofintermediate 1, step D, from(RS)-3-amino-5-(4-chlorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide(1.18 g, 3.11 mmol).

Intermediate 3:3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-iodobenzamide Step A

3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-nitrobenzamide, lightyellow solid (1.25 g, 92%), MS (ISP) m/z=359.1 [(M+H)⁺], mp 172° C., wasprepared in accordance with the general method of intermediate 1, stepA, from 3-(4-chlorophenyl)-5-nitrobenzoic acid (intermediate 2, step A)(1.05 g, 3.78 mmol) and commercially available2-cyclopropylpropan-2-amine (0.45 g, 4.54 mmol).

Step B

3-Amino-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-benzamide, lightyellow solid (0.98 g, 85%), MS (ISP) m/z=329.1 [(M+H)⁺], mp 199° C., wasprepared in accordance with the general method of intermediate 1, stepC, from3-(4-chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-nitrobenzamide (1.25g, 3.48 mmol).

Step C

The title compound, light brown solid (1.0 g, 77%), MS (ISP) m/z=440.1[(M+H)⁺], mp 152° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-benzamide (0.97g, 2.95 mmol).

Intermediate 4:3-(4-Chlorophenyl)-5-iodo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamideStep A

3-(4-Chlorophenyl)-5-nitro-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide,off-white solid (0.63 g, 43%), MS (ISP) m/z=387.1 [(M+H)⁺], mp 180° C.,was prepared in accordance with the general method of intermediate 1,step A, from 3-(4-chlorophenyl)-5-nitrobenzoic acid (intermediate 2,step A) (1.05 g, 3.78 mmol) and commercially available1,1,1-trifluoro-2-methylpropan-2-amine (577 mg, 4.54 mmol).

Step B

3-Amino-5-(4-chlorophenyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide,light yellow solid (0.57 g, 98%), MS (ISP) m/z=357.1 [(M+H)⁺], mp 150°C., was prepared in accordance with the general method of intermediate1, step C, from3-(4-chlorophenyl)-5-nitro-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide(0.63 g, 1.63 mmol).

Step C

The title compound, light yellow solid (0.53 g, 71%), MS (ISP) m/z=468.1[(M+H)⁺], mp 163° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-Amino-5-(4-chlorophenyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide(0.56 g, 1.58 mmol).

Intermediate 5: N-tert-Butyl-3-(4-fluorophenyl)-5-iodobenzamide Step A

3-(4-Fluorophenyl)-5-nitrobenzoic acid, light brown solid (4.33 g, 97%),MS (ISN) m/z=260.1 [(M−H)⁻], mp 182° C., was prepared in accordance withthe general method of intermediate 1, step B, from commerciallyavailable 3-iodo-5-nitrobenzoic acid (5.0 g, 17.1 mmol) and commerciallyavailable (4-fluorophenyl)-boronic acid (2.63 g, 18.8 mmol).

Step B

N-tert-Butyl-3-(4-fluorophenyl)-5-nitrobenzamide, yellow solid (1.03 g,93%), MS (ISP) m/z=317.1 [(M+H)⁺], mp 180° C., was prepared inaccordance with the general method of intermediate 1, step A, from3-(4-fluorophenyl)-5-nitrobenzoic acid (914 mg, 3.50 mmol) andcommercially available 2-methylpropan-2-amine (307 mg, 441 l, 4.20mmol).

Step C

3-Amino-N-tert-butyl-5-(4-fluorophenyl)-benzamide, light yellow solid(0.93 g, 99%), MS (ISP) m/z=287.2 [(M+H)⁺], mp 215° C., was prepared inaccordance with the general method of intermediate 1, step C, fromN-tert-Butyl-3-(4-fluorophenyl)-5-nitrobenzamide (1.03 g, 3.26 mmol).

Step D

The title compound, off-white (0.83 g, 64%), MS (ISP) m/z=398.1[(M+H)⁺], mp 146° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-N-tert-butyl-5-(4-fluorophenyl)-benzamide (0.93 g, 3.25 mmol).

Intermediate 6:N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-iodobenzamide Step A

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-nitrobenzamide, lightbrown solid (1.05 g, 88%), MS (ISP) m/z=343.1 [(M+H)⁺], mp 159° C., wasprepared in accordance with the general method of intermediate 1, stepA, from 3-(4-fluorophenyl)-5-nitrobenzoic acid (intermediate 5, step A)(914 mg, 3.50 mmol) and commercially available2-cyclopropyl-propan-2-amine hydrochloride (0.57 g, 4.20 mmol).

Step B

3-Amino-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide,orange semi-solid (0.95 g, 99%), MS (ISP) m/z=313.2 [(M+H)⁺], wasprepared in accordance with the general method of intermediate 1, stepC, from N-(2-cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-nitrobenzamide(1.05 g, 3.07 mmol).

Step C

The title compound, light orange solid (0.84 g, 66%), MS (ISP) m/z=424.1[(M+H)⁺], mp 144° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide (0.94g, 3.02 mmol).

Intermediate 7:N-tert-Butyl-3-iodo-5-(2-propan-2-ylimidazol-1-yl)-benzamide Step A

N-tert-Butyl-3-nitro-5-(2-propan-2-ylimidazol-1-yl)-benzamide, off-whitesolid (0.97 g, 71%), MS (ISP) m/z=331.2 [(M+H)⁺], mp 166.5° C., wasprepared in accordance with the general method of example 1 fromN-tert-butyl-3-iodo-5-nitrobenzamide (intermediate 1, step A) (1.45 g,4.17 mmol) and commercially available 2-isopropyl-1H-imidazole (918 mg,8.33 mmol).

Step B

3-Amino-N-tert-butyl-5-(2-propan-2-ylimidazol-1-yl)-benzamide, whitesolid (0.83 g, 94%), MS (ISP) m/z=301.2 [(M+H)⁺], mp 256.5° C., wasprepared in accordance with the general method of intermediate 1, stepC, from N-tert-butyl-3-nitro-5-(2-propan-2-ylimidazol-1-yl)-benzamide(0.97 g, 2.94 mmol).

Step C

The title compound, light yellow solid (0.85 g, 72%), MS (ISP) m/z=412.1[(M+H)⁺], mp 169.5° C., was prepared in accordance with the generalmethod of intermediate 1, step D, from3-amino-N-tert-butyl-5-(2-propan-2-ylimidazol-1-yl)-benzamide (0.86 g,2.86 mmol).

Intermediate 8:3-(4-Chlorophenyl)-5-iodo-N-(2-methylbutan-2-yl)-benzamide Step A

3-Iodo-N-(2-methylbutan-2-yl)-5-nitrobenzamide, off-white solid (1.44 g,99%), MS (ISP) m/z=363.0 [(M+H)⁺], mp 117° C., was prepared inaccordance with the general method of intermediate 1, step A, fromcommercially available 3-iodo-5-nitrobenzoic acid (1.17 g, 4.0 mmol) andcommercially available 2-methylbutan-2-amine (0.42 g, 4.8 mmol).

Step B

3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-nitrobenzamide, light brownsolid (0.69 g, 99%), MS (ISP) m/z=347.1 [(M+H)⁺], mp 171.5° C., wasprepared in accordance with the general method of intermediate 1, stepB, from 3-iodo-N-(2-methylbutan-2-yl)-5-nitrobenzamide (0.72 g, 1.99mmol) and commercially available (4-chlorophenyl)-boronic acid (405 mg,2.59 mmol).

Step C

3-Amino-5-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-benzamide, lightyellow solid (0.62 g, 97%), MS (ISP) m/z=317.2 [(M+H)⁺], mp 192° C., wasprepared in accordance with the general method of intermediate 1, stepC, from 3-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-5-nitrobenzamide (1.25g, 3.48 mmol).

Step D

The title compound, light yellow solid (0.65 g, 78%), MS (ISP) m/z=428.1[(M+H)⁺], mp 136° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-5-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-benzamide (0.62 g,1.96 mmol).

Intermediate 9:N-tert-Butyl-3-iodo-5-[4-(trifluoromethyl)-phenyl]-benzamide Step A

N-tert-Butyl-3-nitro-5-[4-(trifluoromethyl)-phenyl]-benzamide, lightbrown solid (0.52 g, 99%), MS (ISP) m/z=367.2 [(M+H)⁺], mp 187.5° C.,was prepared in accordance with the general method of intermediate 1,step B, from N-tert-butyl-3-iodo-5-nitrobenzamide (intermediate 1, stepA) (0.50 g, 1.44 mmol) and commercially available(4-trifluoromethyl-phenyl)-boronic acid (355 mg, 1.87 mmol).

Step B

3-Amino-N-tert-butyl-5-[4-(trifluoromethyl)-phenyl]-benzamide, lightyellow solid (0.48 g, 99%), MS (ISP) m/z=337.2 [(M+H)⁺], mp 228.5° C.,was prepared in accordance with the general method of intermediate 1,step C, fromN-tert-butyl-3-nitro-5-[4-(trifluoromethyl)-phenyl]-benzamide (0.52 g,1.42 mmol).

Step C

The title compound, light yellow solid (0.44 g, 72%), MS (ISP) m/z=448.1[(M+H)⁺], mp 139° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-N-tert-butyl-5-[4-(trifluoromethyl)-phenyl]-benzamide (0.46 g,1.37 mmol).

Intermediate 10:3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-iodo-benzamideStep A

3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-nitrobenzamide,light yellow foam (1.36 g, 72%), MS (ISP) m/z=349.1 [(M+H)⁺], wasprepared in accordance with the general method of intermediate 1, stepA, from 3-(4-chlorophenyl)-5-nitrobenzoic acid (intermediate 2, step A)(1.50 g, 5.40 mmol) and commercially available2-amino-2-methylpropan-1-ol (0.58 g, 6.48 mmol).

Step B

3-Amino-5-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide,light yellow foam (0.54 g, 99%), MS (ISP) m/z=319.2 [(M+H)⁺], mp 150°C., was prepared in accordance with the general method of intermediate1, step C, from3-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-nitrobenzamide(0.60 g, 1.72 mmol).

Step C

The title compound, light yellow foam (0.52 g, 74%), MS (ISP) m/z=430.1[(M+H)⁺], mp 79° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-5-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide(0.52 g, 1.63 mmol).

Example 1N-tert-Butyl-3-(4-chlorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide

A mixture of N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide(intermediate 1) (103 mg, 0.25 mmol), commercially available2-isopropyl-1H-imidazole (55.1 mg, 0.50 mmol) and potassium carbonate(69.1 mg, 500 μmol) in DMSO (1.5 ml) was purged with argon in anultrasonic bath for 5 min at room temperature, N,N-dimethylglycine (10.3mg, 100 μmol) and copper(I)iodide (9.52 mg, 50 μmol) were added, andheated in a sealed tube at 115° C. for 17 h. The reaction mixture wasdiluted with water (10 ml), the precipitate collected by filtration andpurified by flash chromatography on silica gel [heptane/ethyl acetate(20-80%)] to yield the title compound (75 mg, 76%) as off-white foam, MS(ISP) m/z=396.3 [(M+H)⁺].

Example 2 N-tert-Butyl-3-(4-chlorophenyl)-5-imidazol-1-ylbenzamide

The title compound, light yellow foam (76 mg, 86%), MS (ISP) m/z=354.2[(M+H)⁺], was prepared in accordance with the general method of example1 from N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide (intermediate 1)(103 mg, 0.25 mmol) and commercially available 1H-imidazole (34.0 mg,0.50 mmol).

Example 3N-tert-Butyl-3-(4-chlorophenyl)-5-(2-methylimidazol-1-yl)-benzamide

The title compound, light yellow solid (76 mg, 83%), MS (ISP) m/z=368.2[(M+H)⁺], mp 220° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide(intermediate 1) (103 mg, 0.25 mmol) and commercially available2-methyl-1H-imidazole (41.1 mg, 0.50 mmol).

Example 4N-tert-Butyl-3-(4-chlorophenyl)-5-(2-ethylimidazol-1-yl)-benzamide

The title compound, white foam (71 mg, 74%), MS (ISP) m/z=382.2[(M+H)⁺], was prepared in accordance with the general method of example1 from N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide (intermediate 1)(103 mg, 0.25 mmol) and commercially available 2-ethyl-1H-imidazole(48.1 mg, 0.50 mmol).

Example 5N-tert-Butyl-3-(4-chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-benzamide

The title compound, white foam (95 mg, 97%), MS (ISP) m/z=394.3[(M+H)⁺], was prepared in accordance with the general method of example1 from N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide (intermediate 1)(103 mg, 0.25 mmol) and commercially available2-cyclopropyl-1H-imidazole (54.1 mg, 0.50 mmol).

Example 6N-tert-Butyl-3-(4-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide

The title compound, off-white solid (70 mg, 74%), MS (ISP) m/z=380.3[(M+H)⁺], mp 224° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 5) (99.3 mg, 0.25 mmol) and commercially available2-isopropyl-1H-imidazole (55.1 mg, 0.50 mmol).

Example 73-(4-Chlorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide

The title compound, white foam (80 mg, 71%), MS (ISP) m/z=450.2[(M+H)⁺], mp 115.5° C., was prepared in accordance with the generalmethod of example 1 from3-(4-chlorophenyl)-5-iodo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide(intermediate 4) (117 mg, 0.25 mmol) and commercially available2-isopropyl-1H-imidazole (55.1 mg, 0.50 mmol).

Example 83-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide

The title compound, light yellow solid (70 mg, 66%), MS (ISP) m/z=422.3[(M+H)⁺], mp 189° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-iodobenzamide(intermediate 3) (110 mg, 0.25 mmol) and commercially available2-isopropyl-1H-imidazole (55.1 mg, 0.50 mmol).

Example 93-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-ethylimidazol-1-yl)-benzamide

The title compound, off-white solid (70 mg, 69%), MS (ISP) m/z=408.2[(M+H)⁺], mp 183° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-iodobenzamide(intermediate 3) (110 mg, 0.25 mmol) and commercially available2-ethyl-1H-imidazole (48.1 mg, 0.50 mmol).

Example 10N-tert-Butyl-3-(2-ethylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide

The title compound, off-white solid (50 mg, 55%), MS (ISP) m/z=366.2[(M+H)⁺], mp 238° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 5) (99.3 mg, 0.25 mmol) and commercially available2-ethyl-1H-imidazole (48.1 mg, 0.50 mmol).

Example 113-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-methylimidazol-1-yl)-benzamide

The title compound, light yellow solid (70 mg, 71%), MS (ISP) m/z=394.2[(M+H)⁺], mp 180° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-iodobenzamide(intermediate 3) (110 mg, 0.25 mmol) and commercially available2-methyl-1H-imidazole (41.1 mg, 0.50 mmol).

Example 12N-tert-Butyl-3-(4-fluorophenyl)-5-(2-methylimidazol-1-yl)-benzamide

The title compound, off-white solid (80 mg, 91%), MS (ISP) m/z=352.2[(M+H)⁺], mp 208° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 5) (99.3 mg, 0.25 mmol) and commercially available2-methyl-1H-imidazole (41.1 mg, 0.50 mmol).

Example 133-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(2-cyclopropyl-propan-2-yl)-benzamide

The title compound, light yellow foam (90 mg, 86%), MS (ISP) m/z=420.2[(M+H)⁺], mp 90° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-iodobenzamide(intermediate 3) (110 mg, 0.25 mmol) and commercially available2-cyclopropyl-1H-imidazole (54.1 mg, 0.50 mmol).

Example 143-(4-Chlorophenyl)-5-(2-methylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide

The title compound, light yellow solid (80 mg, 76%), MS (ISP) m/z=422.2[(M+H)⁺], mp 199.5° C., was prepared in accordance with the generalmethod of example 1 from3-(4-chlorophenyl)-5-iodo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide(intermediate 4) (117 mg, 0.25 mmol) and commercially available2-methyl-1H-imidazole (41.1 mg, 0.50 mmol).

Example 153-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide

The title compound, light yellow foam (100 mg, 89%), MS (ISP) m/z=448.2[(M+H)⁺], mp 101.5° C., was prepared in accordance with the generalmethod of example 1 from3-(4-chlorophenyl)-5-iodo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide(intermediate 4) (117 mg, 0.25 mmol) and commercially available2-cyclopropyl-1H-imidazole (54.1 mg, 0.50 mmol).

Example 16N-tert-Butyl-3-(2-cyclopropylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide

The title compound, off-white solid (80 mg, 85%), MS (ISP) m/z=378.2[(M+H)⁺], mp 250.5° C. was prepared in accordance with the generalmethod of example 1 from N-tert-butyl-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 5) (99.3 mg, 0.25 mmol) and commercially available2-cyclopropyl-1H-imidazole (54.1 mg, 0.50 mmol).

Example 17N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide

The title compound, white foam (60 mg, 59%), MS (ISP) m/z=406.3[(M+H)⁺], mp 80° C., was prepared in accordance with the general methodof example 1 fromN-(2-cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 6) (106 mg, 0.25 mmol) and commercially available2-isopropyl-1H-imidazole (55.1 mg, 0.50 mmol).

Example 18N-(2-Cyclopropylpropan-2-yl)-3-(2-ethylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide

The title compound, white foam (73 mg, 75%), MS (ISP) m/z=392.3[(M+H)⁺], mp 70° C., was prepared in accordance with the general methodof example 1 fromN-(2-cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 6) (106 mg, 0.25 mmol) and commercially available2-ethyl-1H-imidazole (48.1 mg, 0.50 mmol).

Example 19N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(2-methylimidazol-1-yl)-benzamide

The title compound, off-white solid (78 mg, 83%), MS (ISP) m/z=378.2[(M+H)⁺], mp 184° C., was prepared in accordance with the general methodof example 1 fromN-(2-cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 6) (106 mg, 0.25 mmol) and commercially available2-methyl-1H-imidazole (41.1 mg, 0.50 mmol).

Example 203-(2-Cyclopropylimidazol-1-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide

The title compound, white foam (84 mg, 83%), MS (ISP) m/z=404.2[(M+H)⁺], mp 83° C., was prepared in accordance with the general methodof example 1 fromN-(2-cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 6) (106 mg, 0.25 mmol) and commercially available2-cyclopropyl-1H-imidazole (54.1 mg, 0.50 mmol).

Example 21N-tert-Butyl-3-(2-propan-2-ylimidazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

The title compound, light yellow foam (90 mg, 84%), MS (ISP) m/z=430.3[(M+H)⁺], mp 96.5° C., was prepared in accordance with the generalmethod of intermediate 1, step B, fromN-tert-butyl-3-iodo-5-(2-propan-2-ylimidazol-1-yl)-benzamide(intermediate 7) (103 mg, 0.25 mmol) and commercially available(4-(trifluoromethyl)-phenyl)-boronic acid (61.7 mg, 325 μmol).

Example 22N-tert-Butyl-3-(3-fluoro-4-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide

The title compound, off-white foam (70 mg, 71%), MS (ISP) m/z=394.3[(M+H)⁺], mp 98° C., was prepared in accordance with the general methodof intermediate 1, step B, fromN-tert-butyl-3-iodo-5-(2-propan-2-ylimidazol-1-yl)-benzamide(intermediate 7) (103 mg, 0.25 mmol) and commercially available3-fluoro-4-methylphenylboronic acid (50.0 mg, 325 μmol).

Example 23N-tert-Butyl-3-(3,4-difluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide

The title compound, off-white foam (90 mg, 91%), MS (ISP) m/z=398.2[(M+H)⁺], mp 91.5° C., was prepared in accordance with the generalmethod of intermediate 1, step B, fromN-tert-butyl-3-iodo-5-(2-propan-2-ylimidazol-1-yl)-benzamide(intermediate 7) (103 mg, 0.25 mmol) and commercially available3,4-difluoro-phenylboronic acid (51.3 mg, 325 μmol).

Example 24N-tert-Butyl-3-(4-chloro-3-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide

The title compound, light yellow foam (100 mg, 97%), MS (ISP) m/z=414.2[(M+H)⁺], mp 98° C., was prepared in accordance with the general methodof intermediate 1, step B, fromN-tert-butyl-3-iodo-5-(2-propan-2-ylimidazol-1-yl)-benzamide(intermediate 7) (103 mg, 0.25 mmol) and commercially available4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 325 μmol).

Example 25N-tert-Butyl-3-(4-cyclopropylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide

The title compound, light yellow foam (70 mg, 70%), MS (ISP) m/z=402.3[(M+H)⁺], mp 95° C., was prepared in accordance with the general methodof intermediate 1, step B, fromN-tert-butyl-3-iodo-5-(2-propan-2-ylimidazol-1-yl)-benzamide(intermediate 7) (103 mg, 0.25 mmol) and commercially available4-cyclopropylphenylboronic acid (52.6 mg, 325 μmol).

Example 26N-tert-Butyl-3-(4-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide

The title compound, off-white foam (70 mg, 75%), MS (ISP) m/z=376.3[(M+H)⁺], mp 104° C., was prepared in accordance with the general methodof intermediate 1, step B, fromN-tert-butyl-3-iodo-5-(2-propan-2-ylimidazol-1-yl)-benzamide(intermediate 7) (103 mg, 0.25 mmol) and commercially available4-methylphenylboronic acid (44.2 mg, 325 μmol).

Example 27N-tert-Butyl-3-(4-fluoro-3-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide

The title compound, off-white foam (70 mg, 71%), MS (ISP) m/z=394.3[(M+H)⁺], mp 98.5° C., was prepared in accordance with the generalmethod of intermediate 1, step B, fromN-tert-butyl-3-iodo-5-(2-propan-2-ylimidazol-1-yl)-benzamide(intermediate 7) (103 mg, 0.25 mmol) and commercially available4-fluoro-3-methylphenylboronic acid (50.0 mg, 325 μmol).

Example 28N-tert-Butyl-3-(2-tert-butylimidazol-1-yl)-5-(4-chlorophenyl)-benzamide

A sealed tube was charged withN-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide (intermediate 1) (37.3mg, 0.3 mmol), potassium phosphate (106 mg, 0.5 mmol) andtetrabutylammonium bromide (40.3 mg, 125 μmol), DMSO (1.5 ml) was added,the reaction mixture purged with argon for 5 min in an ultrasonic bathand copper(I)iodide (4.76 mg, 25 μmol) and4,7-dihydroxy-1,10-phenanthroline (10.6 mg, 50 μmol) were added. Themixture was allowed to stir for 24 h at 100° C., diluted with water (5ml), the precipitate was collected by filtration, and purified by flashchromatography on silica gel [heptane/ethyl acetate (20-80%)] to yieldthe title compound as light yellow foam (24 mg, 23%), MS (ISP) m/z=410.2[(M+H)⁺], mp 101° C.

Example 29N-tert-Butyl-3-(4-chlorophenyl)-5-[2-(hydroxymethyl)-imidazol-1-yl]-benzamide

The title compound, light yellow foam (59 mg, 62%), MS (ISP) m/z=384.2[(M+H)⁺], mp 114° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide(intermediate 1) (103 mg, 0.25 mmol) and commercially available(1H-imidazol-2-yl)-methanol (49.1 mg, 0.50 mmol).

Example 303-(4-Chlorophenyl)-5-[2-(hydroxymethyl)-imidazol-1-yl]-N-(2-methylbutan-2-yl)-benzamide

The title compound, off-white foam (71 mg, 71%), MS (ISP) m/z=398.2[(M+H)⁺], mp 76° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-5-iodo-N-(2-methylbutan-2-yl)-benzamide (intermediate8) (107 mg, 0.25 mmol) and commercially available(1H-imidazol-2-yl)-methanol (49.1 mg, 0.50 mmol).

Example 313-(2-tert-Butylimidazol-1-yl)-5-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-benzamide

The title compound, light yellow solid (16 mg, 15%), MS (ISP) m/z=424.3[(M+H)⁺], mp 189.5° C., was prepared in accordance with the generalmethod of example 28 from3-(4-chlorophenyl)-5-iodo-N-(2-methylbutan-2-yl)-benzamide (intermediate8) (107 mg, 0.25 mmol) and commercially available2-tert-butyl-1H-imidazole (37.3 mg, 0.30 mmol).

Example 32N-tert-Butyl-3-(2-tert-butylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide

The title compound, light yellow solid (50 mg, 51%), MS (ISP) m/z=394.3[(M+H)⁺], mp 218° C. was prepared in accordance with the general methodof example 28 from N-tert-butyl-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 5) (99.3 mg, 0.25 mmol) and commercially available2-tert-butyl-1H-imidazole (37.3 mg, 0.30 mmol).

Example 33N-tert-Butyl-3-(2-tert-butylimidazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

The title compound, off-white solid (30 mg, 27%), MS (ISP) m/z=444.3[(M+H)⁺], mp 225° C. was prepared in accordance with the general methodof example 28 fromN-tert-butyl-3-iodo-5-[4-(trifluoromethyl)-phenyl]-benzamide(intermediate 8) (112 mg, 0.25 mmol) and commercially available2-tert-butyl-1H-imidazole (37.3 mg, 0.30 mmol).

Example 34N-tert-Butyl-3-(4-fluorophenyl)-5-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-benzamide

The title compound, white solid (20 mg, 20%), MS (ISP) m/z=396.3[(M+H)⁺], mp 183° C. was prepared in accordance with the general methodof example 28 from N-tert-butyl-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 5) (99.3 mg, 0.25 mmol) and commercially available2-(1H-imidazol-2-yl)-propan-2-ol (63.1 mg, 0.50 mmol).

Example 35N-tert-Butyl-3-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-5-[4-(trifluoromethyl)-phenyl]-benzamide

The title compound, off-white solid (10 mg, 9%), MS (ISP) m/z=446.3[(M+H)⁺], mp 173.5° C. was prepared in accordance with the generalmethod of example 28 fromN-tert-butyl-3-iodo-5-[4-(trifluoromethyl)-phenyl]-benzamide(intermediate 8) (112 mg, 0.25 mmol) and commercially available2-(1H-imidazol-2-yl)-propan-2-ol (63.1 mg, 0.50 mmol).

Example 363-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide

The title compound, white foam (79 mg, 77%), MS (ISP) m/z=410.2[(M+H)⁺], mp 87° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-5-iodo-N-(2-methylbutan-2-yl)-benzamide (intermediate8) (107 mg, 0.25 mmol) and commercially available2-isopropyl-1H-imidazole (55.1 mg, 0.50 mmol).

Example 373-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(2-methylbutan-2-yl)-benzamide

The title compound, light green foam (91 mg, 89%), MS (ISP) m/z=408.3[(M+H)⁺], mp 85° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-5-iodo-N-(2-methylbutan-2-yl)-benzamide (intermediate8) (107 mg, 0.25 mmol) and commercially available2-cyclopropyl-1H-imidazole (54.1 mg, 0.50 mmol).

Example 38(RS)-3-(4-Chlorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide

The title compound, white foam (72 mg, 61%), MS (ISP) m/z=472.2[(M+H)⁺], mp 112° C., was prepared in accordance with the general methodof example 1 from(RS)-3-(4-chlorophenyl)-5-iodo-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide(intermediate 2) (122 mg, 0.25 mmol) and commercially available2-isopropyl-1H-imidazole (55.1 mg, 0.50 mmol).

Example 39(RS)-3-(4-chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide

The title compound, off-white foam (89 mg, 76%), MS (ISP) m/z=470.2[(M+H)⁺], mp 115° C., was prepared in accordance with the general methodof example 1 from(RS)-3-(4-chlorophenyl)-5-iodo-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide(intermediate 2) (122 mg, 0.25 mmol) and commercially available2-cyclopropyl-1H-imidazole (54.1 mg, 0.50 mmol).

Example 40N-tert-Butyl-3-(4-chlorophenyl)-5-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-benzamide

The title compound, light yellow foam (50 mg, 24%), MS (ISP) m/z=412.2[(M+H)⁺], mp 78° C. was prepared in accordance with the general methodof example 28 from N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide(intermediate 1) (207 mg, 0.50 mmol) and commercially available2-(1H-imidazol-2-yl)-propan-2-ol (126 mg, 1.0 mmol).

Example 413-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(2-propan-2-yl-imidazol-1-yl)-benzamide

The title compound, white foam (60 mg, 58%), MS (ISP) m/z=412.3[(M+H)⁺], mp 97° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-iodo-benzamide(intermediate 10) (107 mg, 0.25 mmol) and commercially available2-isopropyl-1H-imidazole (55.1 mg, 0.50 mmol).

Example 423-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide

The title compound, light yellow foam (80 mg, 78%), MS (ISP) m/z=410.2[(M+H)⁺], mp 99° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-iodo-benzamide(intermediate 10) (107 mg, 0.25 mmol) and commercially available2-cyclopropyl-1H-imidazole (54.1 mg, 0.50 mmol).

Example 433-(2-tert-Butylimidazol-1-yl)-5-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide

The title compound, white foam (40 mg, 38%), MS (ISP) m/z=426.2[(M+H)⁺], mp 234° C., was prepared in accordance with the general methodof example 28 from3-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-iodo-benzamide(intermediate 10) (107 mg, 0.25 mmol) and commercially available2-tert-butyl-1H-imidazole (62.1 mg, 0.50 mmol).

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein R^(1′) is CH₃; R¹is methyl, ethyl, CF₃, cyclopropyl, CH₂OH or R^(1′) and R¹ may formtogether with the carbon atom to which they are attached a1,1-dioxo-thiolan-3-yl ring; R² is hydrogen, methyl, ethyl, isopropyl,tertbutyl, cyclopropyl, CH₂OH or C(CH₃)₂OH; R³ is Cl, F, CF₃, cyano,methyl or cyclopropyl; and R⁴ is hydrogen, methyl or F.
 2. A compound ofclaim 1 of formula IA:

or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen,methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH₂OH or C(CH₃)₂OH; R³is Cl, F, CF₃, cyano, methyl or cyclopropyl; R⁴ is hydrogen, methyl orF.
 3. A compound of in claim 2, or a pharmaceutically acceptable saltthereof, wherein the compound is selected from the group consisting of:N-tert-Butyl-3-(4-chlorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;N-tert-Butyl-3-(4-chlorophenyl)-5-imidazol-1-ylbenzamide;N-tert-Butyl-3-(4-chlorophenyl)-5-(2-methylimidazol-1-yl)-benzamide;N-tert-Butyl-3-(4-chlorophenyl)-5-(2-ethylimidazol-1-yl)-benzamide;N-tert-Butyl-3-(4-chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-benzamide;N-tert-Butyl-3-(4-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;N-tert-Butyl-3-(2-ethylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide;N-tert-Butyl-3-(4-fluorophenyl)-5-(2-methylimidazol-1-yl)-benzamide;N-tert-Butyl-3-(2-cyclopropylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide;N-tert-Butyl-3-(2-propan-2-ylimidazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide;N-tert-Butyl-3-(3-fluoro-4-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;N-tert-Butyl-3-(3,4-difluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;N-tert-Butyl-3-(4-chloro-3-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;N-tert-Butyl-3-(4-cyclopropylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;N-tert-Butyl-3-(4-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;N-tert-Butyl-3-(4-fluoro-3-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;N-tert-Butyl-3-(2-tert-butylimidazol-1l-yl)-5-(4-chlorophenyl)-benzamideN-tert-Butyl-3-(4-chlorophenyl)-5-[2-(hydroxymethyl)-imidazol-1-yl]-benzamide;N-tert-Butyl-3-(2-tert-butylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide;N-tert-Butyl-3-(2-tert-butylimidazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide;N-tert-Butyl-3-(4-fluorophenyl)-5-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-benzamide;N-tert-Butyl-3-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-5-[4-(trifluoromethyl)-phenyl]-benzamide;andN-tert-Butyl-3-(4-chlorophenyl)-5-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-benzamide.4. A compound of claim 1 of formula IB:

or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen,methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH₂OH or C(CH₃)₂OH; R³is Cl, F, CF₃, cyano, methyl or cyclopropyl; R⁴ is hydrogen, methyl orF.
 5. A compound of claim 4, or a pharmaceutically acceptable saltthereof, wherein the compound is selected from the group consisting of:3-(4-Chlorophenyl)-5-[2-(hydroxymethyl)-imidazol-1-yl]-N-(2-methylbutan-2-yl)-benzamide;3-(2-tert-Butylimidazol-1-yl)-5-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-benzamide3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamideor3-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(2-methylbutan-2-yl)-benzamide.6. A compound of claim 1 of formula IC:

or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen,methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH₂OH or C(CH₃)₂OH; R³is Cl, F, CF₃, cyano, methyl or cyclopropyl; R⁴ is hydrogen, methyl orF.
 7. A compound of claim 6, or a pharmaceutically acceptable saltthereof, wherein the compound is selected from the group consisting of:3-(4-Chlorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide;3-(4-Chlorophenyl)-5-(2-methylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide;and3-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide.8. A compound of claim 1 of formula ID:

or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen,methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH₂OH or C(CH₃)₂OH; R³is Cl, F, CF₃, cyano, methyl or cyclopropyl; R⁴ is hydrogen, methyl orF.
 9. A compound of claim 8, or a pharmaceutically acceptable saltthereof, wherein the compound is selected from the group consisting of:3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-ethylimidazol-1-yl)-benzamide;3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-methylimidazol-1-yl)-benzamide;3-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(2-cyclopropyl-propan-2-yl)-benzamide;N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;N-(2-Cyclopropylpropan-2-yl)-3-(2-ethylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide;N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(2-methylimidazol-1-yl)-benzamide;and3-(2-Cyclopropylimidazol-1-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide.10. A compound of claim 1 of formula IE:

or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen,methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH₂OH or C(CH₃)₂OH; R³is Cl, F, CF₃, cyano, methyl or cyclopropyl; R⁴ is hydrogen, methyl orF.
 11. A compound of claim 10, or a pharmaceutically acceptable saltthereof, wherein the compound is selected from the group consisting of:(RS)-3-(4-Chlorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;and(RS)-3-(4-chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide.12. A compound of claim 1 of formula IF:

wherein R² is hydrogen, methyl, ethyl, isopropyl, tertbutyl,cyclopropyl, CH₂OH or C(CH₃)₂OH; R³ is Cl, F, CF₃, cyano, methyl orcyclopropyl; R⁴ is hydrogen, methyl or F; or a pharmaceuticallyacceptable salt or acid addition salt, a racemic mixture, or itscorresponding enantiomer and/or optical isomer and/or stereoisomerthereof.
 13. A compound of claim 12, or a pharmaceutically acceptablesalt thereof, wherein the compound is selected from the group consistingof:3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(2-propan-2-yl-imidazol-1-yl)-benzamide;3-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide;and3-(2-tert-Butylimidazol-1-yl)-5-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide.14. A process for the manufacture of a compound of claim 1 of formula I,wherein the process comprises the steps: a) reacting a compound offormula:

with a compound of formula:

to provide a compound of formula I

b) reacting a compound of formula:

with a compound of formula:

to a compound of formula I:

15.-16. (canceled)
 17. A pharmaceutical composition comprising acompound of claim 1 and one or more pharmaceutically acceptableexcipients.
 18. (canceled)
 19. A method for the treatment schizophrenia,bipolar disorder, obsessive-compulsive disorder or autism spectrumdisorder, which method comprises administering a therapeuticallyeffective amount of a compound of formula I according to claim 1, or apharmaceutically acceptable salt thereof, to a human in need of suchtreatment.
 20. (canceled)